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Differential effects of exposure to bisphenol analogues and estradiol on zebrafish host-associated microbiota and behavior
Citation:
Catron, T., S. Keely, N. Brinkman, A. Swank, L. Wehmas, D. Phelps, J. Sobus, J. McCord, E. Wheaton, C. Wood, A. Kvasnicka, S. Gaballah, M. Strynar, AND T. Tal. Differential effects of exposure to bisphenol analogues and estradiol on zebrafish host-associated microbiota and behavior. Microbiome Consortium Symposium, Durham, NC, May 15, 2018.
Impact/Purpose:
Intestinal microbes are thought to play important roles in development of the nervous system. It has been proposed that microbiota can 1) interact with environmental chemicals through bioactivation or detoxification, or 2) be targeted by chemical exposures. This work shows that exposure to bisphenol S, bisphenol A, and bisphenol F, three chemicals that fail to produce toxicity or produce low toxicity in zebrafish, significantly disrupts microbial community structure and function. Exposure to bisphenol AF, bisphenol B, and estradiol, three chemicals that produce developmental toxicity, does not affect microbial community structure or function. Furthermore, exposure to estradiol, a potent estrogen receptor agonist and reference chemical for estrogen receptor activation, causes neurotoxicity only in zebrafish with microbes. Following exposure, colonized zebrafish also contain three times less estradiol relative to microbe-free zebrafish, suggesting that microbes bioactivate estradiol. Exposure to bisphenol A and bisphenol A alternatives does not alter neurobehavior in zebrafish when microbes are either present or absent. Interestingly, zebrafish developmental toxicity was found to be inversely related to disruption of microbiota. The differential chemical effects observed here suggest that current hazard identification strategies have the potential to misestimate risk if interactions between chemicals and microbiota are not considered.
Description:
Host-associated microbiota can biotransform xenobiotics, mediate health effects of chemical exposure, and play important roles in early development. Bisphenol A (BPA) is a widespread environmental chemical that has been associated with adverse endocrine and neurodevelopmental effects, some of which may be mediated by microbiota. Growing public concern over the safety of BPA has resulted in its replacement with structurally similar alternatives. We evaluated whether BPA or BPA alternatives alter microbiota and lead to secondary adverse effects in zebrafish. The classic estrogen receptor agonist 17beta-estradiol (E2) was used as a reference chemical. Zebrafish were developmentally exposed to BPA, Bisphenol AF (BPAF), Bisphenol B (BPB), Bisphenol F (BPF), Bisphenol S (BPS), or E2. At 10 days post fertilization (dpf), toxicity assessments were completed and 16S rRNA gene sequencing was performed to evaluate potential chemical-dependent shifts in microbial community structure and function. To examine whether chemical-induced neurotoxicity was mediated by microbiota, locomotor activity was assessed in colonized and microbe-free zebrafish using a standard light/dark behavioral assay. Based on developmental toxicity at 10 dpf, a range of potencies was observed: BPAF > E2 > BPB > BPF > BPA > BPS. Analysis of 16S rRNA gene sequencing data showed significant concentration-dependent disruption of microbial community structure and enrichment of many microbial functions with exposure to BPS, BPA, or BPF, but not BPB, E2, or BPAF. Colonization-dependent hypoactivity was observed only with E2 exposure. Subsequent tissue collection and analysis of internal E2 concentrations revealed that microbe-free larvae contained three times more E2 then colonized larvae, suggesting that microbes bioactivate E2. Our findings indicate that there is an inverse relationship between microbiota disruption and developmental toxicity early in life and demonstrate novel chemical-microbiota interactions that may add important context to current hazard identification strategies. This abstract does not necessarily reflect EPA policy.